Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Day FR et al. (2015) Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Zhang Y et al. (2020) Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. We developed a polycystic ovary syndrome phenotyping algorithm based on the Rotterdam criteria and applied it to three electronic health records-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual genome-wide association study using the Geisinger's MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1x10^-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analysis. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to characterize protein-protein interaction network. Using the same algorithm based on the Rotterdam criteria, we identified 2,995 patients with polycystic ovary syndrome and 53,599 population controls in total (2,742 cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). We identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8x10^-8) located near SOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10^-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45x10^-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 SNPs with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, while rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using STRING to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1 which has been previously associated with polycystic ovary syndrome. Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4, and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome-gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: ERBB4 Confers Risk for Polycystic Ovary Syndrome in Han Chinese. Peng Y et al. (2017) A recent genome-wide association study (GWAS) of polycystic ovary syndrome (PCOS) in European cohorts has identified six susceptibility loci mapping to 11q22.1 (YAP1), 2p21 (THADA), 11p14.1 (FSHB), 2q34 (ERBB4), 12q21.2 (KRR1), and 5q31.1 (RAD50). The loci of 11q22.1, 2p21 and 11p14.1 have been confirmed to be associated with PCOS in Chinese; whereas the other three new loci (2q34, 12q21.2, and 5q31.1) still need to be evaluated in Chinese. This study was aimed to determine if the three new loci identified in European PCOS also confer risks for PCOS in Han Chinese. We performed a case-control genetic association study comprising 1500 PCOS cases and 1220 age-matched control subjects. Marker SNPs rs1351592 (2q34, ERBB4), rs1275468 (12q21.2, KRR1) and rs13164856 (5q31.1, RAD50) were genotyped using TaqMan-MGB probe assay. Genotyping analysis showed the allele frequency of rs1351592 in gene ERBB4 was significantly different (P = 1.05E-03) between PCOS cases and control group, and remained significant even after BMI adjustment (Padjusted = 2.09E-04). However, the allele frequencies of the other two risk variants, rs1275468 (12q21.2, KRR1) and rs13164856 (5q31.1, RAD50), were not significantly different in the replication cohort. Our results demonstrate that ERBB4, with the strongest association in European PCOS, also confers risk for PCOS in Han Chinese.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: embryonic lethal
Comment: Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Gassmann M et al. (1995) Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Erbb4 regulates the oocyte microenvironment during folliculogenesis. Veikkolainen V et al. (2020) Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genome-wide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood. Since no genetic animal models mimicking all PCOS reproductive features are available, we conditionally deleted Erbb4 in murine granulosa cells under the control of Amh promoter. While we have demonstrated that Erbb4 deletion displayed aberrant ovarian function by affecting the reproductive function (asynchronous oestrous cycle leading to few ovulations and subfertility) and metabolic function (obesity), their ovaries also present severe structural and functional abnormalities (impaired oocyte development). Hormone analysis revealed an upregulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in granulosa cells leads to defective intercellular junctions between the granulosa cells and oocytes, causing changes in the expression of genes regulating the local microenvironment of the follicles. In vitro culture assays reducing the level of Erbb4 via shRNAs confirm that Erbb4 is essential for regulating Amh level. In conclusion, our results indicate a functional role for Erbb4 in the ovary, especially during folliculogenesis and its reduced expression plays an important role in reproductive pathophysiology such as PCOS development.//////////////////